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Thursday, May 10, 2018

Researchers Use a Molecular Trojan Horse to Deliver Chemotherapeutic Drug to Cancer Cells

Riverside: A research team at the University of California, Riverside has
discovered a way for chemotherapy drug paclitaxel to target migrating,
or circulating, cancer cells, which are responsible for the development
of tumor metastases. Until now, paclitaxel has only been used to target rapidly dividing
cancer cells. The team was successful in getting the drug to piggyback
on 123B9, an agent they devised to target an oncogene
called EphA2 (ephrin type-A receptor 2). EphA2 spreads cancer by
allowing malignant cells to migrate from the primary tumor into
circulation and eventually to adhere to other tissues.
“Once this novel tumor-homing agent binds to the EphA2 receptor, the
oncogene functions as a cancer-specific molecular Trojan horse for
paclitaxel, carrying the drug inside the cancel cell, killing the cell,
and thwarting metastasis,” said Maurizio Pellecchia, a professor of biomedical sciences at UCR’s School of Medicine who led the research. “Without the targeting agent, paclitaxel cannot hitch a ride on EphA2.”Study results appear in the Journal of Medicinal Chemistry.

Maurizio
Pellecchia is a professor of biomedical sciences and the Daniel Hays
Endowed Chair in Cancer Research in the School of Medicine at UC
Riverside.Photo credit: UCR School of Medicine.

Tumor metastasis is a leading cause of patient morbidity and
mortality, and no treatments are currently available that specifically
target metastasis formation. Cancer cells depend on a number of
oncogenes, like EphA2, to form metastasis, the medical term for cancer
spreading from the primary site to other regions in the body,
accomplished when cancer cells break away from the primary site, travel
through the blood or lymph system, and form new tumors elsewhere in the
body.
Pellecchia and his colleagues found that when 123B9 binds to the
extracellular region of the EphA2 receptor expressed in cancer cells, it
causes the oncogene to internalize and degrade inside the cell, thus
preventing cancer cells from entering circulation and metastasizing.
“Because this binding causes EphA2 internalization, we also sought to
conjugate 123B9 with paclitaxel and thus direct the drug to migrating
cancer cells,” said Pellecchia, who holds the Daniel Hays Chair in
Cancer Research at UCR.
Recent collaborative work between UCR and Cedars-Sinai Medical Center
in Los Angeles demonstrated that in animal models of human breast
cancer, mice treated with 123B9 that was conjugated with paclitaxel had
significantly fewer circulating cancer cells in the blood compared to
mice that were not treated or even treated with paclitaxel alone.
“Our work predicts that reducing the number of circulating cancer
cells produces less metastasis,” Pellecchia said. “Indeed, in a second
tumor model of metastatic breast cancer, we demonstrated that mice
treated with the EphA2-targeting paclitaxel conjugate presented nearly
no lung metastases, while a large numbers of lesions were observed in
both untreated mice and in mice treated with just paclitaxel.”
Pellecchia said the road to a therapeutic for human trials is still
long and includes the iterative design and synthesis of more potent and
selective agents.
“Nonetheless, the proof of concept studies we have obtained thus far
are extremely encouraging, and we are confident that with proper support
and efforts we could translate our findings into experimental
therapeutics for a variety of solid tumors that are driven by EphA2
overexpression, including breast, lung, prostate, pancreatic, and
ovarian cancers,” said Pellecchia, who serves as the founding director
of the Center for Molecular and Translational Medicine at UCR.
He noted that while these studies solidify UCR’s partnership with
Cedars-Sinai Medical Center, the research team moving forward is
expanding. Already, it includes UCR’s Jikui Song, an assistant professor of biochemistry, and Dr. Samar Nahas, an assistant clinical professor of gynecology and oncology in the School of Medicine.
The study was supported by grants from the National Cancer Institute at the National Institutes of Health.
Pellecchia was joined in the research by Ahmed F. Salem (first
author), Parima Udompholkul, Luca Gambini, and Carlo Baggio at UCR; Si
Wang at the Sanford-Burnham-Prebys Medical Discovery Institute, La
Jolla, Calif.; Sandrine Billet, Jie-Fu Chen, Edwin M. Posadas, and Neil
A. Bhowmick at Cedars-Sinai Medical Center; and Hsian-Rong Tseng at the
Department of Molecular and Medical Pharmacology at UCLA. Salem, Wang,
and Billet made equal contributions to the research.